A large number of children with perinatally-acquired HIV infection are now surviving into adolescence and adulthood. For many of these, HIV infection was not diagnosed and treated until significant immunological abnormalities were already present. In addition, nearly all had poor suppression of HIV replication with the less potent treatment regimens available during their pre-adolescent years. We hypothesize that prolonged and poorly controlled HIV infection throughout childhood in these individuals will lead to premature immunological senescence in early to mid-adulthood, perhaps by accelerating the physiological thymic involution that occurs in childhood and adolescence. The general goal of the studies proposed is to better understand the immunological status and prognosis of long-term survivors of perinatal HIV infection, and to identify possible therapeutic strategies to promote a normal, healthy lifespan for this growing population of infected youths. Taking scientific advantage of the availability of a large local cohort of perinatally infected adolescents, we are proposing studies to examine the balance between the pathogenic properties of HIV, the suppressive and selective power of antiretroviral therapy, and the regenerative capacity of the immune system that exists in these individuals. The specific aims are: 1) To use in vivo labeling methods and other approaches to compare quantitative parameters of thymopoiesis from adolescents/young adults with perinatal HIV infection with those from two age-matched control groups: seronegative subjects, and youths with HIV infection acquired via recent adult behaviors; 2) To evaluate the relationship between these parameters of thymopoiesis, and the pol and nef genotypes and the replication properties of patient HIV isolates, and 3) To examine the magnitude and breadth of cellular immune responses of perinatally infected adolescents to HIV and common infectious agents (including cytomegalovirus, influenza, and Epstein-Barr Virus) compared to the age matched controls. [unreadable] [unreadable]